COVID-19 Stroke Apical Lung Examination Study: A Diagnostic and Prognostic Imaging Biomarker in Suspected Acute Stroke.

BACKGROUND AND PURPOSE: Diagnosis of coronavirus disease 2019 (COVID-19) relies on clinical features and reverse-transcriptase polymerase chain reaction testing, but the sensitivity is limited. Carotid CTA is a routine acute stroke investigation and includes the lung apices. We evaluated CTA as a potential COVID-19 diagnostic imaging biomarker. MATERIALS AND METHODS: This was a multicenter, retrospective study (n = 225) including CTAs of patients with suspected acute stroke from 3 hyperacute stroke units (March-April 2020). We evaluated the reliability and accuracy of candidate diagnostic imaging biomarkers. Demographics, clinical features, and risk factors for COVID-19 and stroke were analyzed using univariate and multivariate statistics. RESULTS: Apical ground-glass opacification was present in 22.2% (50/225) of patients. Ground-glass opacification had high interrater reliability (Fleiss κ = 0.81; 95% CI, 0.68-0.95) and, compared with reverse-transcriptase polymerase chain reaction, had good diagnostic performance (sensitivity, 75% [95% CI, 56-87]; specificity, 81% [95% CI, 71-88]; OR = 11.65 [95% CI, 4.14-32.78]; P < .001) on multivariate analysis. In contrast, all other contemporaneous demographic, clinical, and imaging features available at CTA were not diagnostic for COVID-19. The presence of apical ground-glass opacification was an independent predictor of increased 30-day mortality (18.0% versus 5.7%, P = .017; hazard ratio = 3.51; 95% CI, 1.42-8.66; P = .006). CONCLUSIONS: We identified a simple, reliable, and accurate COVID-19 diagnostic and prognostic imaging biomarker obtained from CTA lung apices: the presence or absence of ground-glass opacification. Our findings have important implications in the management of patients presenting with suspected stroke through early identification of COVID-19 and the subsequent limitation of disease transmission.

A survey of UK percutaneous lung biopsy practice: current practices in the era of early detection, oncogenetic profiling, and targeted treatments.

AIM: To ascertain current percutaneous lung biopsy practices around the UK. MATERIALS AND METHODS: A web-based survey was sent to all British Society of Thoracic Imaging (BSTI) and British Society of Interventional Radiology (BSIR) members (May 2017) assessing all aspects of lung biopsy practice. Responses were collected anonymously. RESULTS: Two hundred and thirty-nine completed responses were received (28.8% response rate). Of the respondents, 48.5% worked in a teaching hospital and 51.5% in a district general hospital, while 32.6% (78/239) were specialist thoracic radiologists, 29.2% (70/239) "general" radiologists with a thoracic subspecialty interest, and 28% (67/239) interventional radiologists. Of the respondents, 30.1% (72/239) did not require pre-biopsy lung function tests (PFTs); 45.6% (108/237) stopped aspirin before the procedure; 97.5% primarily use computed tomography (CT) guidance for biopsy and 88.7% (212/239) perform core needle biopsy (CNB); and 86.6% of radiologists use a co-axial technique. There was wide variation in the number of samples routinely taken with most radiologists performing 1-2 passes (55.9%) or 3-4 passes (40.8%). Sixty-four percent reported using chest drain prevention techniques to minimise the impact of iatrogenic pneumothorax, with needle aspiration most frequent (43.9%). Timing of post-biopsy chest radiography (CXR), performed by 95.8% (228/239), also varied greatly: most commonly at either 1 hour (23%), 2 hours (24.7%), or 4 hours (22.6%). Moreover, the time of patient discharge after uncomplicated biopsy was variable, although the majority (66.1%) discharge patients after ≥4 hours. CONCLUSION: There are striking variations among surveyed UK radiologists performing lung biopsy in decision-making, pre-biopsy work-up, post-biopsy monitoring, management of pneumothorax, and discharge. The results suggest a need for new updated national percutaneous lung biopsy guidelines.

Does testicular microlithiasis matter? A review.

Radiologists who regularly undertake ultrasound of the testes will occasionally encounter testicular microlithiasis (TM). Currently, the management of a patient with TM is a conundrum for clinician and radiologist alike: there are reported associations between TM and primary testicular malignancy and infertility. However, there is no consensus on the appropriate follow-up (clinical, radiological or otherwise) of patients with TM. Furthermore, it is not clear whether the incidence of de novotumours is increased in patients with pre-existing TM. Similarly, there is limited evidence to support the association with infertility. Not surprisingly, algorithms for the follow-up of patients with TM on ultrasound have been difficult to formulate.

Scrotal calcification: ultrasound appearances, distribution and aetiology.

This pictorial review illustrates the ultrasound appearances of scrotal calcification, distinguishing between intratesticular and extratesticular calcification. Intratesticular calcification may be due to phleboliths, spermatic granulomas or vascular calcification, or it may occur in association with tumours. Extratesticular calcification is more frequently encountered and is usually related to previous inflammatory disease of the epididymis. Testicular microlithiasis, a rare condition characterized by multiple scattered echogenic foci within the testis, is produced by the formation of microliths from degenerating cells in the seminiferous tubules. Testicular microlithiasis has been demonstrated as an incidental finding as well as in association with both benign and malignant tumours of the testis.

The initiating factors of late preconditioning in skeletal muscle.

PURPOSE: The goal of these studies was to determine the initiating factors for late preconditioning in the microcirculation of skeletal muscle. MATERIALS AND METHODS: The cremaster muscle of male Sprague-Dawley rats underwent 4 h of ischemia and then 60 min of reperfusion. Ischemic preconditioning (IPC) consisted of 45 min of ischemia but was done 24 h before the 4 h of ischemia. To mimic the effects of IPC in the late phase, adenosine (ADO) or sodium nitroprusside (SNP) was given 24 h before the prolonged ischemia via local intraarterial infusion. To block the effects of IPC in the late phase, 8-sulfophenyl-theophylline (a nonspecific ADO receptor blocker) or N(W)-nitro-l-arginine (a nonselective nitric oxide synthase antagonist) was given prior to IPC. Microvascular response to IPC and pharmacological preconditioning were determined by measuring arteriole diameters and capillary perfusion using intravital microscopy. RESULTS: Administration of ADO or SNP on day 1 without IPC produced a similar microvascular protection against prolonged ischemia/reperfusion on day 2 as that induced by IPC alone. In contrast, blocking ADO receptors or nitric oxide synthase on day 1 just prior to IPC eliminated the IPC-induced microvascular protection seen on day 2. In addition, inhibition of nitric oxide synthase on day 1 diminished the protection induced by ADO, but blocking ADO receptors on day 1 did not compromise the protection induced by SNP. CONCLUSION: The results from these studies suggest that up regulation of ADO is the initiating factor with secondary up regulation of nitric oxide in late preconditioning. Both ADO and nitric oxide contribute to initiating microvascular protection in the late phase of IPC.

Leukocyte-endothelial adhesion is impaired in the cremaster muscle microcirculation of the copper-deficient rat.

Dietary copper deficiency impairs the function of both the vascular endothelium and circulating leukocytes. In the current study, leukocyte-endothelium adhesion was observed in the in vivo cremaster muscle microcirculation of copper-adequate and copper-deficient rats. Male, weanling Sprague-Dawley rats were fed purified diets that were either adequate (5.6 microg/g) or deficient (0.3 microg/g) in copper. Adhesion was stimulated with the inflammatory mediators tumor necrosis factor-alpha and bradykinin, and the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine. Intravascular adhesion of leukocytes to the vascular endothelium was significantly attenuated in the copper-deficient group in response to all three agonists. These results occurred without any difference in intravascular wall shear rate between the dietary groups. Based on previous work, we propose that the attenuated response is caused by either decreased expression of adhesion molecules on leukocytes and endothelial cells or by inhibition of the endothelial cell calcium signaling associated with copper deficiency.

Percutaneous excision of a facet joint cyst under CT guidance.

We report a patient with a cyst of the posterior inter-articular joint that was decompressed using a bone biopsy Temno needle.

Initiation of microvascular protection by nitric oxide in late preconditioning.

The authors hypothesized that nitric oxide is induced by a brief period of ischemia/reperfusion (ischemic preconditioning, IPC) on postoperative day (POD) 1, and that this released nitric oxide is responsible for initiating a delayed microvascular protection against a prolonged period of ischemia in skeletal muscle on POD day 2. The cremaster muscle of male Sprague-Dawley rats underwent 4 hr of ischemia, and then 60 min of reperfusion. IPC consisted of 45 min of ischemia but was done 24 hr before the prolonged ischemia. Local intraarterial infusion of sodium nitroprusside (SNP, a donor of nitric oxide) or Nw-nitro-L-arginine (L-NA, a nonselective nitric oxide synthase antagonist) were also given 24 hr before prolonged ischemia. Arteriole diameters and capillary perfusion were measured using intravital microscopy. Four groups were compared: 1) control; 2) IPC; 3) SNP + sham IPC; and 4) L-NA + IPC. Four hours of ischemia followed by reperfusion created a significant vasoconstriction and capillary no-reflow in the microcirculation of cremaster muscles. These alterations were largely prevented by IPC. Local intraarterial infusion of SNP without IPC created a similar microvascular protection to that induced by IPC alone. In contrast, intraarterial infusion of L-NA prior to IPC eliminated the IPC-induced microvascular protection. In conclusion, in late preconditioning, nitric oxide contributes to the initiation of a delayed microvascular protection against prolonged ischemia in skeletal muscle.

Endothelial cell calcium mobilization to acetylcholine is attenuated in copper-deficient rats.

Dietary copper deficiency significantly attenuates nitric oxide (NO)-mediated vascular smooth muscle relaxation and vasodilation. There is evidence for both increased inactivation of the NO radical by superoxide anion, and oxidative damage to the endothelium where NO is produced. The current study was designed to examine the NO synthetic pathway in the endothelium during copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient (CuD, 0.4 mg Cu/kg diet) diet for four weeks. Cremasteric arterioles (approximately 100 microm diameter) were isolated and used for the experiments. Western blot analysis of the arteriole endothelial nitric oxide synthase (eNOS) concentration did not show a difference between dietary groups. Acetylcholine (Ach)-induced vasodilation was significantly reduced in the CuD group both before and after pretreatment with the eNOS substrate L-arginine. Endothelial intracellular calcium ([Ca2+]i) stimulated by 10(-6) M Ach was significantly inhibited in the arterioles from CuD rats. Coincident with the inhibition of [Ca2+]i and vasodilation was a depression of vascular Cu/Zn-SOD activity and an increase in plasma peroxynitrite activity. These data suggest that endothelial Ca2+ signaling and agonist-stimulated NO-mediated vascular dilation are likely reduced by increased oxidative damage in copper-deficient rats.

Docosahexaenoic acid reverses cyclosporin A-induced changes in membrane structure and function.

The use of a fish oil vehicle for cyclosporin A (CsA) can decrease the toxic effects of CsA but the mechanism is unclear. Here we examine the mechanism by which docosahexaenoic acid (DHA), a fish oil-derived polyunsaturated fatty acid, can alter the toxic effects of CsA on mouse organ function, endothelial macromolecular permeability, and membrane bilayer function. Mice given CsA and fish oil showed increased liver toxicity, kidney toxicity, incorporation of DHA, and evidence of oxidized fatty acids compared to control animals. We hypothesized that the toxic effects of CsA were primarily a result of membrane perturbation, which could be decreased if DHA were not oxidized. The presence of CsA (10 mol%) alone increased dipalmitoylphosphatidylcholine membrane permeability by seven fold over control (no CsA, no DHA). However, if non-oxidized DHA (15 mol%) and CsA were added to the membrane, the permeability returned to control levels. Interestingly, if the DHA was oxidized, the antagonistic effect of DHA on CsA was completely lost. While CsA alone increased endothelial permeability to albumin, the combination of non-oxidized DHA and CsA had no effect on endothelial macromolecular permeability. However the combination of oxidized DHA and CsA was no different than the effects of CsA only. CsA increased the fluorescence anisotropy of DPH in the liquid crystalline state of DPPC, while DHA decreased fluorescence anisotropy. However the combination of CsA and DHA was no different than DHA alone. We conclude that non-oxidized DHA can reverse the membrane perturbing effects of CsA, and the increases in endothelial macromolecular permeability, which may explain how fish oil is capable of decreasing the toxicity of CsA.

Platelet-activating factor contributes to postischemic vasospasm.

BACKGROUND: The purpose of the present study was to determine if platelet-activating factor is an important mediator that produces vasospasm during reperfusion after ischemia in skeletal muscle. MATERIALS AND METHODS: A vascular isolated cremaster muscle in male Sprague-Dawley rats was coupled with local intraarterial drug infusion as a model to study microcirculation responses to ischemia/reperfusion injury. Arteriole diameters and capillary perfusion were measured using intravital microscopy. Group 1: platelet-activating factor dose response. Group 2: Effects of a cyclooxygenase inhibitor; indomethacin, and a thromboxane synthetase inhibitor, imidazole, on the response to platelet-activating factor. Group 3: Effects of nitric oxide synthesis inhibitor; N(omega)-nitro-L-arginine methyl ester, on the response to platelet-activating factor. Group 4: Effects of a platelet-activating factor receptor antagonist, CV-3988, indomethacin, and imidazole after 4 h of warm ischemia and reperfusion. RESULTS: Intraarterial infusion of platelet-activating factor produced a dose-related but mild vasoconstriction. Pretreatment with indomethacin or imidazole resulted in significant vasodilation actually emanating from platelet-activating factor infusion. Nitric oxide inhibition (with N(omega)-nitro-L-arginine methyl ester) enhanced the vasoconstriction produced by platelet-activating factor. Pretreatment with CV-3988, indomethacin, or imidazole significantly attenuated ischemia/reperfusion-induced vasospasm and capillary no-reflow in the cremaster muscles. CONCLUSIONS: Ischemia/reperfusion-induced vasoconstriction is at least in part mediated by platelet-activating factor and thromboxane A(2).

Bradykinin and alpha-thrombin increase human umbilical vein endothelial macromolecular permeability by different mechanisms.

Bradykinin and alpha-thrombin both increase endothelial macromolecular permeability, however the mechanism for this effect is unclear. Human umbilical vein endothelial cell (HUVEC) permeability to human serum albumin was increased by 1 microM alpha-thrombin (AT) or bradykinin (BK), but the kinetics of the permeability response were different. Intracellular calcium mobilization of HUVEC by AT was increased, yet BK had no effect on intracellular calcium. Distribution of F-actin and content was increased by AT as early as 10 minutes after administration, yet BK had no affect on F-actin when compared to control. We hypothesized that BK may increase HUVEC permeability by producing matrix metalloproteinase-2 (MMP-2). The AT-treated HUVEC produced an intermediate 64 kDa MMP-2, whereas BK-treated HUVEC increased the intermediate 64 kDa MMP-2 and also an active 62 kDa MMP-2. Pre-treatment of the HUVEC with tissue inhibitor of matrix metalloproteinase-2 slightly decreased the AT-induced increase in macromolecular permeability and completely inhibited the BK-induced increase in macromolecular permeability.

A new continuous monitoring system for simultaneous measurements of intracellular calcium and either endothelial permeability or leukocyte extravasation.

OBJECTIVE AND DESIGN: We have developed a continuous monitoring system that will quantify lymphocyte extravasation or intercellular permeability with intracellular calcium measurements in a single preparation. MATERIALS: Human microvascular endothelial cells, human lymphocytes and histamine. TREATMENT: Endothelial barrier function and intracellular calcium were examined upon application of either human lymphocytes (1 x 10(5) cells/ml) or histamine (1 microM). METHODS: Endothelial cells labeled with FURA-2 were examined for both changes in endothelial barrier function and mobilization of intracellular calcium using fluorescence spectroscopy and ratio imaging, respectively. RESULTS: Increases in endothelial intracellular calcium occur in the first minute and are followed by increases in endothelial intercellular permeability to albumin (5-7 min) or lymphocytes (15-20 min). Approximately 60 min following calcium mobilization, there was a second and larger extravasation. CONCLUSION: The continuous monitoring system expands our understanding of the time course of the permeability and extravasation events to mobilization of endothelial intracellular calcium.

Endocytosis of heparin-binding protein (CAP37) is essential for the enhancement of lipopolysaccharide-induced TNF-alpha production in human monocytes.

Heparin-binding protein (HBP), also known as CAP37, is a proteolytically inactive serine protease homologue that is released from activated granulocytes. However, HBP is not a biologically inactive molecule but rather a multifunctional protein with properties that include the enhancement of LPS-induced TNF-alpha production from monocytes. We have previously demonstrated that HBP is internalized in monocytes. In the current study, we hypothesize that HBP is internalized in monocytes via endocytosis, and this internalization is an important mechanism by which HBP enhances LPS-induced TNF-alpha release. Using whole blood from healthy donors and flow cytometry, we found that colchicine (0.1-10 mM), cytochalasin D (1000 microM), NH4Cl (10-50 mM), and bafilomycin A1 (0.1-3 microM) significantly reduced the affinity of FITC-HBP for CD14-positive monocytes. Using isolated human monocytes and ELISA, we found that colchicine (0.1 mM), cytochalasin D (30 and 300 microM), NH4Cl (30 mM), and bafilomycin A1 (1 microM) significantly reduced the effect of HBP (10 microg/ml) to enhance LPS (10 ng/ml)-induced TNF-alpha release after 24 h. These findings demonstrate that internalization of HBP in monocytes is essential for the enhancement of LPS-induced TNF-alpha release. Transport of HBP to an activating compartment depends on intact F-actin polymerization and endosomal acidification, an important mechanism for endosomal protein sorting and trafficking.

Mechanisms of leukocyte-mediated tissue injury induced by interleukin-2.

In this review we discuss the effects of interleukin-2 (IL-2) therapy on trafficking of leukocytes and platelets to normal organs. The use of animal models has allowed the elucidation of events leading to damage and/or dysfunction of normal tissues after IL-2 administration. These studies have shown that acute toxicity induced by IL-2 is mediated primarily by neutrophils. Chronic toxicity results from the adhesion and transmigration of activated lymphocytes into normal organs. Platelet-derived microvascular thrombosis also contributes to the vascular toxicity of IL-2. A better understanding of these mechanisms may lead to the development of interventions that will significantly improve the therapeutic efficacy of IL-2.

Enhanced pulmonary expression of CXC chemokines during hepatic ischemia/reperfusion-induced lung injury in mice.

BACKGROUND: Hepatic ischemia/reperfusion injury during both hepatic resection and transplantation may lead to local and systemic organ dysfunction. Proinflammatory mediators released by Kupffer cells during the initial phase of ischemia/reperfusion are thought to be involved in the development of neutrophil-mediated lung injury. However, the precise factors involved in lung recruitment of neutrophils are unclear. The objective of current study was to determine whether the CXC chemokines, macrophage inflammatory protein-2 (MIP-2) and KC, contribute to pulmonary neutrophil recruitment and injury following hepatic ischemia/reperfusion. METHODS: C57BL/6 mice were subjected to 90 min of partial hepatic ischemia and 3, 6, and 9 h of reperfusion. Neutrophil accumulation in lung was assessed by lung content of myeloperoxidase (MPO). MIP-2 and KC mRNA were measured using RT-PCR. Lung edema was quantified by wet to dry weight ratios. RESULTS: Three hours after hepatic reperfusion, serum levels of tumor necrosis factor-alpha were increased. Lung expression of both MIP-2 and KC mRNA was also increased at this time. Both MIP-2 and KC mRNA expression remained elevated 9 h after reperfusion, although levels of MIP-2 mRNA were significantly lower than at 3 h. Pulmonary recruitment of neutrophils was increased within 3 h after reperfusion, but returned to baseline levels by 9 h. Lung edema was increased 3 and 9 h after reperfusion. Neutralization of MIP-2 or KC with antibody significantly decreased lung edema 9 h after reperfusion. CONCLUSIONS: These data suggest that mediators released during hepatic ischemia/reperfusion induce the expression of MIP-2 and KC in the lung. In addition, it appears that MIP-2 and KC contribute to lung neutrophil accumulation and the associated pulmonary injury following hepatic ischemia/reperfusion.

Relationship between dietary copper concentration and acetylcholine-induced vasodilation in the microcirculation of rats.

Dietary copper deficiency has been shown to significantly reduce acetylcholine (Ach)-induced vascular smooth muscle relaxation. The current study was designed to examine the relative relationship between dietary copper and the vasodilator response to Ach in the microcirculation of the rat. Male weanling rats were fed a purified basal diet supplemented with 6.0, 3.0, 1.5 or 0.0 microg Cu/g diet for 4 weeks to provide an adequate, two marginal, and deficient intakes of dietary copper. Arteriole dilation in response to increasing concentrations of acetylcholine (10(-7) to 10(-4) M) was measured in the in vivo cremaster muscle microcirculation for each dietary group. Liver copper and both aortic and erythrocyte Cu,Zn-SOD activity were used as indices of systemic copper status. Dilation to the increasing concentrations of Ach was only different in the 0 microg Cu supplemented group compared to the copper-adequate control values. However, the combined results showed an exponential increase in 10(-5) M Ach-induced vasodilation as liver copper concentration increases from 0 microg Cu/g dry wt. This relationship suggests that dilation is attenuated at liver Cu concentrations below 5 microg/g dry wt. The results indicate that Ach-induced vasodilation is copper-dependent but that the pathway is not very sensitive to short-term marginal restriction of copper intake.

Quantitative image analysis of F-actin in endothelial cells.

OBJECTIVE: Filamentous actin (F-actin) plays a central role in maintaining endothelial barrier function. Thrombin and histamine, two inflammatory mediators that increase endothelial permeability, can alter F-actin production and distribution. In this study, we use a newly developed image analysis technique to show that these two inflammatory mediators differentially alter F-actin structure. METHODS: Human umbilical vein endothelial cells were grown to confluence and treated with either histamine (1 microM), thrombin (1 microM) or the agonist's vehicle. The endothelium was stained with BODIPY-phallodin, and digitized images were taken of the treated cells. The digitized images of individual human umbilical vein endothelial cells (HUVEC) were imported into a F-actin image analysis program (FAAP) and converted to layers, each one pixel thick. The program then determined the mean gray level (which corresponded to the amount of F-actin) in each layer starting from the outside of the cell (layer 1) and progressing in one pixel layer increments towards the center of the cell (layer 32). RESULTS: Both inflammatory mediators increased endothelial F-actin production, however, the distribution of the actin was different. Thrombin increased the presence of stress fibers, while also decreasing peripheral banding actin. In contrast, histamine had no effect on peripheral actin compared to control, but did increase the presence of F-actin stress fibers. CONCLUSIONS: These results establish that thrombin and histamine alter endothelial F-actin production in different locations within the cell, which can be quantified using an image analysis program.